The overall goals of this project are to characterize the determinants of vascular structure and function, and evaluate their effects on cardiovascular morbidity and mortality 1. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. Aortic PWV was measured at baseline in 2488 older adults. Over an average of 4.6 years of follow-up, 265 deaths occurred with 111 categorized as cardiovascular in cause. Higher aortic aPWV quartile was associated with both total mortality (P = 0.010) and CV mortality (P=.006), independent of age, gender, race, SBP, known CV disease, creatinine, cholesterol and smoking. Thus, among a generally healthy, well-functioning, community dwelling population, aPWV, a marker of arterial stiffness, is associated with higher total and CV mortality (Circulation 2005;111(25):3384-3390). 2. Hypertension (HTN) is generally considered a risk factor for arterial stiffening because chronically increased blood pressure determines structural and functional changes in arterial walls. However, arterial stiffening may also predispose to the development of HTN. We therefore evaluated whether arterial stiffening predicts the development of HTN in normotensive healthy adults. Pulse wave velocity (PWV), a non-invasive index of arterial stiffness, was measured in 364 volunteers from the Baltimore Longitudinal Study of Aging who were normotensive at baseline. After a mean follow-up of 5.1+/-2.9 years, 75 subjects (21%) developed HTN. Variables that were significantly associated with the development of HTN included older age, higher PWV, body mass index, systolic blood pressure, diastolic blood pressurre, and triglycerides, and lower HDL cholesterol. Because of a significant interaction between age and PWV, we examined younger (age<50 years) and older age groups separately. We found that in healthy normotemsive younger, but not older, adults, higher arterial stiffness is an independent predictor of future HTN. Thus, screening for arterial stiffening may identify a subset of normotenisve younger individuals at increased risk for developing HTN, in whom early interventions may be indicated. 3. Intimal medial thickness (IMT) and vascular stiffness have been shown to be independent predictors of adverse cardiovascular events. The metabolic syndrome (MS) is defined as the clustering of 3 or more of the cardiovascular risk factors of dysglycemia, hypertension, dyslipidemia, and obesity. We evaluated whether the clustering of multiple components of the MS has a greater impact on these vascular parameters than individual components of the MS in 471 participants from the Baltimore Longitudinal Study on Aging who were without clinical cardiovascular disease and not on antihypertensive therapy. MS was an independent predictor of increased carotid IMT and stiffness, and conferred a disproportionate increase in carotid IMT (16%) and stiffness (32%,) compared to controls even after taking into account each individual component of the MS. This suggests that the components of the MS interact to synergistically impact vascular thickness and stiffness. Future studies should examine whether the excess cardiovascular risk associated with the MS is, in part, mediated through the amplified alterations in these vascular properties (J Am Coll Cardiol. 2004;43(8):1388-95). 4. The prevalence of the metabolic syndrome, a potent risk factor for cardiovascular diseases, has not been adequately explored in older individuals. Moreover, 2 sets of criteria have been proposed for the definition of the metabolic syndrome, one by the World Health Organization (WHO) and one by the National Cholesterol Education Program (ATPIII). We found that the prevalence of this syndrome in a subgroup of 2175 older participants from the Cardiovascular Health Study (CHS) free of cardiovascular disease at baseline to be 28.1% by ATPIII criteria, and 21.0%, by WHO criteria. The two sets of criteria provided concordant classification for 80.6% of participants. Multivariate Cox propotional hazard models showed that the metabolic syndrome defined with the ATPIII criteria, but not with the WHO criteria, was an independent predictor of coronary or cerebrovascular events, and was associated with a 38% increased risk (HR 1.38, 95%CI 1.06-1.79, p< 0.01). Thus, as defined by the ATPIII criteria, the metabolic syndrome yields independent prognostic information, even after adjusting for traditional cardiovascular risk factors and the individual domains of the metabolic syndrome (Diabetes Care 2005;28(4):882-887). 5. Increased thickness and stiffness of large arteries may contribute to why aging is the most important risk for cardiovascular diseases. Several large studies have shown that moderate alcohol consumption reduces the risk for heart disease and stroke. We examined whether alcohol consumption alters age-associated increases in arterial stiffness and intimal medial thickness (IMT). A total of 563 volunteers from the Baltimore Longitudinal Study of Aging had carotid duplex ultrasonography with measurements of IMT and an arterial stiffness index. Alcohol intake was assessed by a standard questionnaire. A U-shaped relationship was found between alcohol intake and stiffness index, with the lowest index in moderate drinkers (1 ? 9.9 drinks per week); this relationship persisted after adjustment for cardiovascular risk parameters. Moderate drinkers showed ~ 50% less age-associated increase in arterial stiffness than heavy drinkers and nondrinkers, both before and after adjusting for other cardiovascular risk factors. A significant positive u-shaped relationship was found between alcohol intake and IMT, which did not persist after adjustment for risk factors. Thus, light to moderate alcohol intake favorably modulates aging of the arterial tree. This effect may explain in part the J- or U-shaped relationship between alcohol intake and cardiovascular disease (Am J Cardiol. 2005;95(8):1006-10). 6. Arterial thickness and stiffness increase with advancing age, and are increasingly recognized as risk factors for cardiovascular morbidity and mortality. Because these complex traits are likely to be affected by a multiplicity of genetic and environmental factors, the search for novel genes that may underlie these phenotypes will require genome wide linkage and association studies. As a first step, we evaluated the heritability of blood pressure and central arterial structure and function in a founder population, i.e. one with high degrees of interrelatedness among its individuals due to limited external admixture. We recruited 6,148 subjects (57% women, 711 families), representing over 60% of the total population aged 14-102, from a cluster of 4 towns on the island of Sardinia. Heritabilities were assessed with simple variance components models, which assume that all similarities between genetic factors are due to additive genetic effects. The narrow heritability estimates for systolic BP, diastolic BP, DiamD, IMT and PWV, adjusted for sex, age and age2, are 0.258, 0.187, 0.443, 0.185 and 0.226 respectively, and indicate that 18% to 44% of the variance can be attributed to genetic factors. A significant difference in heritability between young (age<42 years) and older persons was only observed for systolic BP (0.09 vs 0.30, p<0.05), suggesting an interaction between age and the contribution of genes to variations in this trait. Thus, in this study of a large founder population, indexes of arterial structure and function show robust heritability estimates, indicating that genome wide linkage and association studies will likely succeed in identifying genes that contribute to the variance in these traits.